N-substituted derivatives of the pyridone series



.4 pyrones may serve.

' Patented Dec. 26,

' PATENT; ;...Q1F'g E' ,U-N T D TATE- N -SUBSTI'IUTED DERIVATIVES OF'THEPYRIDONELVSERIESY. 5,5

1 Karl Miescher and Ernest llre ch, Basel; Switzeb" land,assignors tothe firm Society of Chemical" lndustry'inBasle, Basel, SwitzerlandNvlliravring} Application July 28, 1930, serial g No. 471, 416, and inSwitzerland August 10,,

The present invention relatesv to new N-substituted derivatives of thepyridone seriesuseful in therapeutics. Thenew productsare formed byconverting compounds containingthe pyridone 5 nucleus, the nuclearnitrogen of which is linked by direct action of an 'alkylene polyhalideor an alkylenehalogenhydrin or an alkylene monohalide, suchas anallylhalide, wherebyin the two latter cases halogen is introduced inknown manner by substitution or addition into the alkyl. By the actionof ammonia or an amine, N-substituted halogen-alkylpyridone is convertedinto aminoalkylpyridone.

The new derivatives may alsoflbe obtained by converting the compoundscontaining the 2- or 4-hydroxypyridine J nucleus 'into their basicethers or their derivatives and isomerizing the V ethers by simplewarming.

A'furtherform of the process consists in:ca.us-

ing the compounds containingthe pyridinenu-j;

cleus'having a free 2- or 4-position; orrsubstitution products-thereof,to'react with'an' ester of an amino-alcohol and oxidizing'the productofthis reaction. A chemical or electrolytic process of oxidation may beused. Y i E Another process of making the new'compou'nds consists incausing. derivatives containing the 4,0 pyrone nucleus or substitutionproducts of such derivatives to react with an alkylene-polyamine havingat least one primary 'amino-group. 'As parent materials for-theinvention" both dine or isoquinoline series. I

As reactive esters of aminoalcohols may be used, for example, aminoalkylestersof hydrohalogenic or of aromatic sulfo acids.

' The new compounds are'u'seful' as. such, oras intermediate products,for therapeutical'purposes.

The following examples-illustrate the inveneat Part be n by eisht=. .1;

monoand poly-cyclic 'pyridines or pyridones or I A v The parent"materialsmay also belong, for example, "tothe quin;oline, acrir a nter-546.4 parts of sodium 2 -pyrido'ne are heated a toluene solution togetherwith parts of chlorethyldiethylamine until the reaction is at an end.

The solvent is expelled and the N-diethylaminoethyl-2-pyridone of theiormula .1

rCHrNU h Hs): ,c is separated by fractionationfromZ-diethylaminoethoxypyridine which has been iormed at the same time; v

(The N-diethylaminoethyl-2-pyridone is 'a colorless oil of boiling point127 C. at-l mm; pressure. Its colorless water and melts at 74" C. andfat"1485 0; when anhydrous. I The base and its salts: are freely soluble in-Example 2- I Equivalent quantitiesof .pyridine andchlorethyldiethylamino-hydrochloride are heated together for some timeat about 125 C.. 150.2 parts of the product of the reactionare dissolvedin Water and after addition of "32 parts of sodium hydroxide thesolution is -mixed gradually in the coldwith an aqueous solutionofi npparts of potassium. ferricyaliide. When oxidation has,

occurred the diethylaminoethyI- Z pyridone is ex-j tracted by means ofbenzene and this solvent is then expelled. Bytdistillation the base isobtainedin pure form It is identical with thebase obtained in accordancewith Example 1.'

The'oxidation may'fbecarriedout in another 1 manner,, for example;electrolytically;

mono-hydrochloride crystallizes with one "molecular proportion of:

ther 'b' obtained by heating Z-diethyIamino Q ethoxy-pyridine'lJOQZZQ-Z'TO" C., or by causing N- fl-bromo-ethyl-2 pyridone to reactwith diethylamine. For the production ,of the ,B-bromoethyl-2-pyridonethe'*iadditive compound of ethylene-'chloro-hydrine t0; pyridine isoxidized to form p-hydrox y -ethyl 2;pyridoneof melting acrannmeL-is.hea edto220721193 Qwherebyigqmthe formula erization isproduced. The new base, namely N-diethylaminoethyl-2-pyridone-3-oarboxylic acidanilide of the formuladistills at 205 C. under 0.3 mm. pressure. It is soluble in organicsolvents and also in acids. Its monohydrochloride melts at 195 C. and isfreely soluble in water.

Example 4 Z-diethylaminoethoxy-lepidine is heated at 220-300" C. Afterisomerization has occurred, the viscid base is distilled. It boils at183 C. under 2 mm. pressure, and gradually becomes solid on standing.The N-diethylaminoethyllepidone thus produced of the formula is solublein organic solvents and in acids. Its mono-hydrochloride melts at 115 C.and dissolves freely in water.

Example 5 boxylic aoid-anilide thus produced of the formula NJHPGHr-N'wiI M forms colorless crystals which melt at 154? C.

Its monohydrochloride is freely soluble in water and melts at 258? C.

Example 6 2-diethylaminoethoXy 3;-phenyl 4 quinolinecarboxylic aciddiethylamide is heated to. 250- 300 C. When isomer'ization has occurred,the lSI-diethylaminOethyl-Z-quinolone 3 phenylcarboxylic aciddiethylamide thus produced'of carom-Mom) is distilled. It boils at 220C. at 0.05 mm. pressure. From petroleum ether or ethyl acetate itcrystallizes in colorless crystals which melt at 118 C. The base issoluble in benzene, in ether, in alcohol and in acids. Its colorlessmonohydrochloride melts at 148 C. with decomposition. The 2-diethylaminoethoXy-3-phenyl-4- quinoline-carboxylic acid-,diethylamide(which is a yellow oil yielding a hydrochloride which melts at 154 C.)may be made by reaction of 2-chloro- .3-phenyl-4-quinoline carboxylicacid diethylamide with sodium diethylaminoethanol.

' Example 7 parts of l-pyrone are dissolved in 100 parts of water andthe solution is mixed with one of 100 parts of unsymmetricaldiethyl-ethylenediamine in 100 parts of water. The mass becomes v hotand yellow brown. After it has been boiled O 0 ll I! o loHzN(o2H5 2boils at 175 C. at 0.03 mm. pressure. It is a yellow, thick oil which isfreely soluble in water to an alkaline solution. I

I Example 8 An aqueous solution of 111 parts ofpphthalimido-ethyl-pyridinium-abromide of the formula after additionof55 parts of sodium hydroxide, is gradually mixed with an, aqueous.solution of 220 parts of potassium ferricyanide. After the oxi: dationis complete, the formed Z-pyridone-N: ethyl-phthalamic acid is separatedby acidification of the solution. When crystallized from alcohol itmelts at 135-137 C. When heated to a higher-temperature it loses waterand changes into the 2-pyridone-N-ethyl-phtha1imide of melting point205C. g g

145 parts of 2-pyridor1e-N-ethyhphthal amic acid are saponifiedbyboiling with concentrated hydrobrom-ic acid. The separated phthalic acidis filtered off and the. filtrateevaporated. By crystallization of theresidue from alcohol the hydro-bromide of N -aminoethyl-2-py ridone ofthe formula H a Y is obtained in colorless crystals of melting point 15cagain-8'12 203 C. The hydrochloride melts at 183 C. Both salts are veryeasily soluble in water.

Example 9 An aqueous solution of 111 parts of -phthalimido-propyl-pyridinium-chloride of the formula-:

after addition of 55 parts 01 sodium hydroxide, is gradually mixed witha solution of 220 parts of potassium ferricyanide. -A'fterf-theoxidation is complete, the reaction liquid is acidified and evaporatedto drynessin a vacuum. The formed 2-pyridone-N-propyl-phthalamic acid isextracted with alcohol." By dehydrationit may be con: verted into the2-pyridone}N propyl-phthalirnide of melting point 225910.; '30 parts ofthe 2-pyridone-N}propy1phthal amic acid are saponifled by boiling withhydro chloric acid of v1'7 per' cent. strength. ifIheseparated phthalicacid-is filtered "oft and the filtrate evaporated. By crystallization ofthe' residue from alcohol, the N -ami'nopropyl- 2pyridone-hy drochlorideof the formula,

obtained colorless :bfgmelting 181-1820; It is very easilyrsolubleinwater.

om-onhmcm oHr-CHPN CHg -CH CIHI ' O C H5 ylic acid diethylethylenediamide.

CHI-CHI is completely separated an oily form by addition of alkali.

most organic solvents. With acids it forms neutral salts which aresoluble in water. In like manner there, can be obtained, forexample, thefollowing derivatives:

It distils-at l75-178 C. at 1.5 mm. 7 pressure as a light yellow oil. Itis soluble 1. N dimethylaminoethyl 2 pyridone 3 car-- boxylicacid-anilide. Mono hydrochloridez orless tirystalsof melting point 218?C. o I 1 2,. N- dibutylaminoethyl-2 -pyridone 3 carboxylic acid-anilide,Mono-hydrochloride: colorless crystals of melting point ;l81.,C.;; 4 1,3. N.- piperidinoethyl-Z-pyridone 3 carboxylic acid-.anilide. Monohydrochloride: colorless crystalsof melting point215 C. V t

.4; .N-diethylaminoethyl-2-pyridone 3 carbox ylic acid-phenetidideQMono-hydrochloride: colo e crysta -10 n p n 1 C-; i A

5, N-diethylaminoethyl-2 -pyridone 3 carboxylic acid- N-ethyl-anilide.Mono-hydrochloride: colorless crystals of melting; point .102 C H 6.N-diethylaminoethyl-2-pyridone 3- carbox- Di-hydrocolorless crystals .01V melting point colchloride:

86 0. I r t '7. N -diethylaminoethyl-2-pyrid0ne 5 carboxylicacid-anilide. Colorless crystals: melting point of the base 10 0-102 C;t

8. N- diethylaminoethyl 2 i quinolone. Yellow oil boiling at 168-170" C.at 2 mm. pressure.

, ,9. N-diethylaminoethyl-G-ethoxy 2 quinolone.

Yellowish oilgboiling ati19200 C. :at 2 m n pressu'r'e.",fiThe-compounds of the foregoing table corre spondwith; thef ollowingiormulasz 0H1 (EBPCHPNWIHOI "ea ery-CHECK,"

- OH -CHz-OHa-CH:

(7) Ca lyn-0&1 (8) CHq-OHr-NKlzHa): CHa-CHRNWI 7HzCHrN( i a)a What weclaim is:- 3. The pyridones of the general formula 1. The pyridones ofthe general formula Y Yr p 0 V hi 7 02B g p I OHrCHr-N V A..V N v IC2135 V I V whereinv the Ysmay stand for hydrogen, Y1 or V v v Y2 mayalso stand for phenyl' or methyl and Y1, wherein A represents analkylene chain contam- V ing at least two carbon atoms, and R1 and R2 ori avgmup'flcoNxm Wherem x' y meanhydrogen or alkyl, or'together maystand hydrogen .phenyL alkyl or dlethylammoethyl for an alkylene chainto form a heterocyclic six gig i f i or fi i member ring, or may alsostand for the phthaloyl S f' nzenermg' W 0 pro s radical, and whereinthe Y's may stand for treatedfwiltlh :g water'soluble salts and h droen, Y or Y ma also stand for hen lor a'miuse u erapeu. I m ethy l andY1, Y: or Y3 for a group 00 1 139, T I?dletliylammoethyl'z'pyndone"g'carWhemin X may be hydrogen, phenyl; alkyl or boxyhc acid amhde of theformula dlethylammoethyl, and wherein Y1 and Yzor Y: C no 1 and Y4 mayalso stand for part of a benzene ring,

which products treated with acids form watersolfible salts, and areuseful in therapeutics.

2. The pyridones of thegeneral formulawherein R1 and Rsmean hydrogen or,or together may stand for an alkylene chain to form a heterocyclic sixmember ring, or

may also stand for thephthaloylradical, and

wherein the Ys may stand'for hydrogen, Y1 or Y2 may also stand forphenyl or methyl and Y1, Y2 or Y3 for a group -CONX2, wherein X may behydrogen, phenyl, alkyl or diethylaminoethyl,

and wherein Y1 and Y2 or Y3 and Y; may also stand for partvof a benzenering, which products treated with acids form water-soluble salts, andare useful in therapeutics.

an oil of boiling point 205 C. at 0.3 mm. pressure, 5 soluble inorganicsolvents and in acids, and forming 1a: monohydrochloride of' meltin'gpoint 195 C., which product is useful in therapeutics.

5. The N-diethylaminoethyl-2-pyridone of the a colorless oil of boilingpoint 127 C. at 1 mm. pressure, soluble in water and in organicsolvents, a and forming a water-soluble mono-hydrochloride of meltingpoint 148 C. when anhydrous, which product is useful in therapeutics.

. KARL MIESCHER.

ERNEST URECH.

